SUMMARY Huntington disease (HD) is a neurodegenerative disorder caused by an abnormal expansion of a CAG repeat in the first exon of the huntingtin gene resulting in a mutant protein with a poly-glutamine expansion. Although mutant huntingtin (mut-Htt) is expressed ubiquitously in the brain, neurodegeneration occurs selectively in the striatum and, to a lesser degree, the cortex. We propose that a key factor in the region-specific vulnerability in HD is a reduction in the expression of FoxP1, a neuroprotective protein that is expressed selectively in medium spiny neurons of the striatum and to a relatively lower level in pyramidal neurons of the cortex. Consistent with our hypothesis, FoxP1 expression is reduced in the striatum of HD patients and HD mouse models. Elevating FoxP1 expression in cultured neurons protects them from mut-Htt toxicity, while knocking down its expression induces death in otherwise healthy neurons. The overall objective of the proposal is to understand the mechanism underlying the reduced expression of FoxP1 in dying neurons and the mechanism by which FoxP1 maintains the survival of neurons normally. Although almost all studies on FoxP1 have focused on a 90 kDa form of the protein called isoform-A, the brain expresses two other major isoforms ? isoforms C and D. The significance of these isoforms as well as other members of the FoxP family that are expressed in the adult striatum will be studied. Finally, we will extend our tissue culture studies to mice and examine whether elevated expression of FoxP1 protects mice from HD and whether the reduced striatal size in brain-specific FoxP1 conditional mice (cKO) is due to neuronal loss. The specific aims of this proposal are: Aim 1: Role of histone deacetylase-3 (HDAC3) and methyl CpG binding protein-2 (MeCP2) in the downregulation of FoxP1 expression in dying neurons. Aim 2: Aim 2: Identify downstream targets of FoxP1 that mediate its protective effect against mut-Htt neurotoxicity. Aim 3: To examine contribution of major FoxP1 isoforms and of FoxP2 and FoxP4 to neuronal survival. Aim 4: Examine the effects of modulating FoxP1 levels on the regulation of neurodegeneration and neuronal survival in vivo. There are currently no effective treatment strategies for the abnormal neuronal loss that occurs in HD. Successful completion of this project has the potential to provide new avenues for the development of a therapy to reduce or stop neurodegeneration in HD.